Cyanoalkyl



United States Patent 3,124,594 N-(CYANOALKYL)-ENDO-PERHYDRO-4,7-METHANOISOINDOLES James W. Bolger, Canoga Park, Calitl, assignor toRiker Laboratories, Inc., Northridge, Calif., a corporation of DelawareNo Drawing. Filed July 27, 1962, Ser. No. 213,004 5 Claims. (Cl.260-319) This invention relates to compositions of matter classified inthe art of chemistry as substituted isoindoles.

The invention sought to be patented resides in the concept of a chemicalcompound in which there is attached to the nitrogen atom of anendo-perhydro-4,7- methanoisoindole nucleus or its hereinafter disclosedequivalents a cyano-lower alkyl group.

As used throughout the specification and in the claim the terms loweralkyl and lower alkylene embrace straight and branched chain alkyl andalkylene radicals, respectively, containing 1 to 6 carbon atoms and theterm cyano denotes the monovalent CN radical.

The tangible embodiments of this invention, possess the inherent generalphysical characteristics of being, in the form of their acid additionsalts, white crystalline solids. Spectral data reveal no unsaturationexcept as present in the nitrile group. The aforementioned physicalcharacteristics, taken together with the nature of the startingmaterials and the mode of synthesis, positively confirm the structure ofthe compounds sought to be patented.

The tangible embodiments of this invention possess I the inherentapplied use characteristics of having significant pharmacologicalactivity as anti-Parkinson and anti-hypertensive agents as determined byrecognized and accepted pharmacological test procedures, and, inaddition are valuable chemical intermediates in the preparation of othersubstituted isoindoles having significant pharmacological activity. Forexample treatment of these compounds with hydroxylamine yields thepharmacologically active N-amidoximo-lower alkyl-endo-perhydro-4,7-methanoisoindoles which are described and claimed in my applicationentitled N-Amidoximo-Alkyl-Endo-Perhydro- 4,7-Methanoisoindoles, SerialNo. 213,047, filed July 27, 1962.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same as follows:

The starting materials for the compounds of this invention,N-(halo-lower-alkyl)-endo-perhydro-4,7-methanoisoindoles and their7a-substituted equivalents are prepared according to the methoddescribed in my application entitled N-(Haloalkyl)-Endo-Perhydro-4,7-Methanoisoindoles, Serial No. 213,050, filed July 27, 1962. The startingmaterials are prepared as described in my aforementioned application bytreatment of N-(hydroxy-lower alkyl)-endo-perhydro-4,7-methanoisoindoleswith a thionyl halide or with a hot hydrohalic acid in the presence ofan inert solvent.

The preparation of the tangible embodiments of this invention isillustrated as follows:

where A is lower alkylene, R is hydrogen or its hereinafter disclosedequivalent and X is halogen.

Starting materials hearing at the 7aposition a lower alkyl or phenylgroup, or such group bearing one or more substituents such as loweralkoxy, halogen, trifluoromethyl, or lower alkyl in the case of phenyl,are the full equivalent of the N-halo-loweralkyl-endoperhydro-4,7-methano starting materials in the foregoingreaction sequence, thereby to produce 7a-substituted N-cyano-lower-alkylfinished products which have the same utility asN-cyano-loWer-alkyl-endo-perhydro-4,7- methanoisoindoles.

The reaction depicted hereinabove is carried out by treating thestarting material with an alkali metal cyanide such as, for example,sodium cyanide, according to the method described by Friedman andSchlechter (J. Org. Chem. 25:877 (1960).

Alternately, such N-(cyano alkyl) substituted isoindoles can be preparedby the treatment of the 7a-substituted or unsubstituted isoindole havinga hydrogen substituent on the ring nitrogen atom with an unsaturatednitrile having a terminal double bond, such as acrylonitrile.

The tangible embodiments of this invention can, if desired, be convertedinto their non-toxic pharmaceutically acceptable acid addition andquaternary ammonium salts by conventional procedures. Typical acidaddition salts include the hydrochloride, hydrobromide, citrate,maleate, sulfate, nitrate and the like. Typical quaternary ammoniumsalts are those formed with such alkyl halides as methyl iodide, ethylbromide, n-hexyl bromide and the like. Such salts are the fullequivalents of the free bases and are included within the scope of thisinvention.

The tangible embodiments of this invention, either as the free base orin the form of a non-toxic pharmaceutically acceptable acid addition orquaternary ammonium salt, may be combined with conventional diluents andcarriers, to form such dosage forms as tablets, capsules, solutions,suspensions, suppositories and the like.

EXAMPLE 1 (a) N-(2'-Cyanoethyl)-End0-Perhydro-4,7-Methan0- isoindoleHydrochloride Endo-perhydro 4,7-methanoisoindole hydrochloride (49.4 g.,0.288'mole) is converted to the free base by dissolving it in a stronglyalkaline solution and extracting with ether. The ether extract is driedwith anhydrous magnesium sulfate and then concentrated in vacuo. Water(4 1111.) is added to the ethereal residue and sufficientdimethylformamide is added to solubilize the mixture. The mixture isstirred and heated at 80 C. while acrylonitrile (15.3 g., 0.288 mole) isadded dropwise. The reaction mixture is kept at 80 C. for one hour,cooled and then fractionally distilled in vacuo. Yield: 47 g. (86%), RP.115-117 C./l mm. Hg. The free base dissolved in ether is converted tothe hydrochloride salt with gaseous hydrogen chloride, M.P. 237238 C. V

Analysis-Calculated for C H N Cl (M.W. 226.75): C, 63.56%; H, 8.45%; Cl,15.64%. Found: C, 63.76%; H, 8.47%; 01, 15.39%.

(b) N-(2-Cyan'oelhyl)-N-Methyl-End0-Perhydr0-4,7- MethanoisoindoleIodide N (2 cyanoethyl)-endo-perhydro-4,7-methanoisoindole hydrochloride(15 g., 0.0662 mole), prepared as described in step a, is dissolved in50 ml. of water and made basic with concentrated sodium hydroxide. Theresulting basic solution is extracted with ether. The ether extract isdried over anhydrous magnesium sulfate and the ether is removed byevaporation. The residue is mixed with 75 ml. of acetone and 15 ml. ofmethyl iodide, then allowed to stand at room temperature for 5 hours. Awhite crystalline solid appears which is recrystallized frommethanol/ether (anhydrous). Yield: 18.5 g. (84%), M.P. 201 C. (d).

Analysis.Calculated for C H N I (M.W. 332.24): C, 47.00%; H, 6.37%; I,38.20%. Found: C, 47.16%; H, 6.31%; I, 38.02%.

EXAMPLE 2 N-(3'-Cyan0propyl)- nd0-Perhydro-4,7-Mcrhan0isoindoleHydrochloride N (3 chloropropyl)-endo-perhydro-4,7-methanoisoindolehydrochloride (25 g., 0.1 mole) is converted to the free base and addedslowly to a rapidly stirred, hot (100 C.) solution of dimethylsulfoxide(80 ml.) containing sodium cyanide (5.4 g., 0.11 mole). The temperatureis kept constant for 2 hours, then the reaction mixture is cooled and100 ml. of water is added. The product is extracted with ether and theether is then removed by evaporation leaving an oil which is distilledin vacuo. The product distilled at 120-125 C./1 mm. Hg. Thehydrochloride salt is made in ether with gaseous hydrogen chloride andthe resulting white powder is recrystallized from ethanol/ether(anhydrous). Yield: 16.5 g. (67%), M.P. 205206 C.

Analysis.Calculated for C H N Cl (M.W. 240.78): C, 64.83%; H, 8.79%; Cl,14.72%. Found: C, 64.75%; H, 8.79%; Cl, 14.76%.

The following example illustrates the preparation of other tangibleembodiments of this invention.

EXAMPLE 3 N (2 '-Cyanoethyl -7a-Methyl-End0-Perhydro4, 7- Methanoisoindole Hydrochloride N (2chloroethyl)-7a-methyl-endo-perhydro-4,7- methanoisoindole hydrochloride(10 g., 0.040 mole) is converted to the free base and added slowly to arapidly stirred, hot C.) solution of dimethylsulfoxide (40 ml.)containing sodium cyanide (2.13 g., 0.0435 mole). The temperature iskept constant for 2 hours, then the reaction mixture is cooled and 100ml. of water is added. The product is extracted with ether and the etherremoved by evaporation. The hydrochloride salt is made in ether withgaseous hydrogen chloride and the resulting product is recrystallizedfrom ethanol. Yield: 5.7 g. (59%), M.P. 225 C.- (d).

Analysis.-Calculated for C H N Cl (M.W. 240.78): C, 64.84%; H, 8.79%;CI, 14.73%. Found: C. 64.59%; H, 8.81%; Cl, 14.80%.

The subject matter which the applicant regards as his invention isparticularly pointed out and distinctly claimed as follows:

1. A compound of the formula wherein R is a member selected from thegroup consisting of hydrogen and lower alkyl and A is lower alkylene.

2. N (2 cyanoethyl)-endo-perhydro-4,7-methaoisoindole.

3. N (2' cyanoethyl-N-methyl-endo-perhydro-4,7- methanoisoindole iodide.

4. N (3' cyanopropyl)-endo-perhydro-4,7-methanoisoindole.

5. N (2' cyanoethyl)-7a-methyl-endo-perhydro-4,7- methanoisoindole.

No references cited.

1. A COMPOUND OF THE FORMULA